This invention relates to compositions of matter and to methods for producing them. The several aspects of this invention relate to novel derivatives of some of the known prostaglandins, for example, prostaglandin F.sub.1.sub..alpha. (PGF.sub.1.sub..alpha.), prostaglandin F.sub.2.sub..alpha. (PGF.sub.2.sub..alpha.), prostaglandin F.sub.3.sub..alpha. (PGF.sub.3.sub..alpha.), prostaglandin dihydro F.sub.1.sub..alpha. (dihydro-PGF.sub.1.sub..alpha.), their 15.beta. epimers, and their racemates, and to novel methods for producing those novel prostaglandin-type derivatives. In particular the novel prostaglandin-type derivatives of this invention are carboxyacylated at the C-15 position.
Each of the above-mentioned known prostaglandins is a derivative of prostanoic acid which has the following structure and atom numbering: ##STR1## A systematic name for prostanoic acid is 7-[(2.beta.-octyl)-cyclopent-1.sub..alpha.-yl]heptanoic acid.
PGF.sub.1.sub..alpha. has the following structure: ##STR2## PGF.sub.2.sub..alpha. has the following structure: ##STR3##
PGF.sub.3.sub..alpha. has the following structure: ##STR4##
Dihydro-PGF.sub.1.sub..alpha. has the following structure: ##STR5##
The prostaglandin formulas mentioned above each have several centers of asymmetry. Each formula represents the particular optically active form of the prostaglandin obtained from certain mammalian tissues, for example, sheep vesicular glands, swine lung, and human seminal plasma, or by reduction or dehydration of a prostaglandin so obtained. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. The mirror image of each formula represents a molecule of the enantiomer of that prostaglandin. The racemic form of the prostaglandin consists of equal numbers of two types of molecules, one represented by one of the above formulas and the other represented by the mirror image of that formula. Thus, both formulas are needed to define a racemic prostaglandin. See Nature 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins. For convenience hereinafter, use of the terms "PGF.sub.1.sub..alpha. ", "PGF.sub.2.sub..alpha. ", and the like, will mean the optically active form of that prostaglandin with the same absolute configuration as PGE.sub.1 obtained from mammalian tissues. When reference to the racemic form of any of these prostaglandins is intended, either the word "racemic" or the prefix "dl" will precede the prostaglandin name, thus, "racemic PGF.sub.1.sub..alpha. " or "dl-PGF.sub.2.sub..alpha. " and the like.
In formulas I, II, III, IV, and V, as well as in the formulas given hereinafter, broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring.
Furthermore, in formulas II-V, the broken line attachment of the hydroxy to the C-15 carbon atom indicates the alpha configuration, i.e. below the plane of the paper. Hereinafter, compounds with epi (R) configuration for the hydroxy at C-15 are so designated by using "15-beta" in the name. If 15-beta (15.beta.) does not appear in the name, the natural configuration for the C-15 hydroxy, identified as the S configuration for PGE.sub.1, to be assumed.
PGF.sub.1.sub..alpha., PGF.sub.2.sub..alpha., PGF.sub.3.sub..alpha., and dihydro-PGF.sub.1.sub..alpha. and their esters and pharmacologically acceptable salts, are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. A few of those biological responses are systemic arterial blood pressure raising in the case of the PGF.sub..alpha. compounds as measured, for example, in anesthetized (pentobarbital sodium) pentolinium-treated rats with indwelling aortic and right heart cannulas; stimulation of smooth muscle as shown, for example, by tests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; activity on the central nervous system; decrease of blood platelet adhesiveness as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen.
Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in birds and mammals, including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.
For example, these compounds are useful in mammals, including man, as nasal decongestants. For this purpose, the compounds are used in a dose range of about 10 .mu.g. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.
The PGF.sub..alpha. compounds are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range about 0.005 to about 20 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.
The PGF.sub..alpha. compounds are especially useful as additives to blood, blood products, blood substitutes, and other fluids which are used in artificial extracorporeal circulation and perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about .001 to 10 mg. per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.
The PGF.sub..alpha. compounds are useful in place of oxytocin to induce labor in pregnant female animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is infused intravenously at a dose of 0.01 to 50 .mu.g. per kg. of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started. An alternative route of administration is oral.
The PGF.sub..alpha. compounds are useful for controlling the reproductive cycle in ovulating female mammals, including humans and animals such as monkeys, rats, rabbits, dogs, cattle, and the like. By the term ovulating female mammals is meant animals which are mature enough to ovulate but not so old that regular ovulation has ceased. For that purpose, PGF.sub.2.sub..alpha., for example, is administered systemically at a dose level in the range 0.01 mg. to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Intravaginal and intrauterine are alternative routes of administration. Additionally, expulsion of an embryo or a fetus is accomplished by similar administration of the compound during the first third of the normal mammalian gestation period.